Compounds for synthesizing steroids



United States Patent COMPOUNDS FOR SYNTHESIZING STEROIDS William S.Knowles, Kirkwood, Mo., assignor to Monsanto Chemical Company, St.Louis, Mo., a corporation of Delaware No Drawing. Application March 30,1953, Serial No. 345,699

12 Claims. (Cl. 260-514) This invention relates to methods and novelcompounds useful in the synthesis of A -bisdehydro-norprogesterone which17-aldehyde steroid may be represented by the structural formula CHO CHa12 A Wis 16 14 15 ketone, which may be represented by the structuralformula However, the processes which have been suggested in itspreparation from tricyclic ketone have been found expensive,procedurally lengthy and cumbersome.

5 It is an object of this invention to provide a less expensive and lesscumbersome process for the synthesis of the 17-a1dehyde steroid. It is afurther object of this invention to provide a process for the synthesisof the 17-aldehyde steroid from 1,8a-dimethyl, A -decahy- 20drophenanthren-Z-one which compound is derived from a compound hereinreferred to as tricyclic ketone. It is a still further object of thisinvention to provide new and novel compounds useful in the preparationof steroids, such as the adrenal cortical hormones. Further objects willbecome apparent hereinafter.

The sequence of steps or series of reactions proceeding to the17-aldehyde steroid for purposes of this invention is outlinedschematically in the following diagram, the novel steps and compounds ofthe present invention comprising those represented in proceeding from1,8a-dimethyl, A -decahydrophenanthren-Z-one (Compound II) to3-keto-16,17-dihydroxy-A -D-homoandrostadiene (Compound IX) of theillustrative diagram.

on. on: CHgCHO l --CH CHO X XI GHO CH:

As indicated by the foregoing diagram the 17-aldehyde steroid can beobtained by means of a relatively simple synthesis. The tricyclic ketone(Compound I) employed in the preparation of the 1,8a-dimethyl, A-decahydrophenanthren-Z-one reactant of this invention may be readilyprepared in accordance with the procedure of R. B. Woodward, J. A. C.8., vol. 74, p. 4223 (1952). As illustrative of the tricyclic ketonereactants contemplated are:

dl-Anti-transl ,8a-dirnethyl, nenthren-Z-one (M. P. 72-73 C.)

d-Anti-trans-l,Sa-dimethyl, A -octahydrophenanthren-2-one (M. P. 4244C.)

l-Anti-trans-l,8a-dimethyl, A -octahydrophenanthren-2-one (M. P. 4-2-44"C.)

The 1,8a-dimethyl, n -decahydrophenanthren-Z- one reactant of thisinvention is prepared by the addition of one molecule of hydrogen to the9-10 double bond of the tricyclic ketone (Compound 1), without at thesame time adding hydrogen to the 6-7 double bond and/ or the l0al doublebond. This step is conveniently carried out by the method described inco-pending application Serial No. 339,470, filed February 27, 1953, ofHarold Raffelson, which method comprises passing hydrogen into asolution of the tricyclic ketone containing dispersed therein apalladium catalyst, until one molar equivalent of hydrogen is absorbed.As illustrative of this step is the following:

A -octahydrophe- Example 1 Approximately 10 parts by weight ofdl-anti-trans1,8adimethyl-A -octahydrophenanthren-Z-one (M. P. 72-73 C.)is admixed in a suitable reaction vessel with approximately 80 parts byweight of 95% ethanol, approximately 2.0 parts by weight of a 5% aqueoussodium hydroxide solution, and approximately one part by weight of a 2%palladium-strontium carbonate catalyst (which had been previouslyreduced). While agitating, gaseous hydrogen is passed into the mixtureat about C. and at substantially atmospheric pressure. After absorptionof substantially one molar equivalent of hydrogen, which takes about 1.2hours, the catalyst is filtered ofl. and the filtrate is neutralizedwith dilute sulfuric acid and is then subjected to vacuum distillation.The residue is then taken up with benzene, and is then washed withseveral small portions of water. The layers are separated and theorganic layer is subjected to vacuum distillation. A substantially 100%yield of a colorless oily product identified asdl-anti-trans-l,8a-dimethyl-A -decahydrophenanthren-Z-one is obtained.

Example ll Approximately 22.8 parts by weight ofl-anti-trans-1,8adimethyI-A -octahydrophenanthren-2-one (M. P. 42-44 C.)is admixed in a suitable reaction vessel with approximately parts byweight of isopropanol, approximately 2.85 parts by weight of a 2%palladium-strontium carbonate catalyst (which had been previouslyreduced) and approximately 2.3 parts by weight of a 10% potassiumhydroxide solution. While agitating, gaseous hydrogen is passed into themixture at about 25 C. until approximately one molar equivalent ofhydrogen is absorbed, which takes about 1.2 hours. The catalyst isfiltered off and the filtrate is neutralized with dilute hydrochloricacid and subjected to vacuum distillation. The residue is then washedwith several small portions of water and is then subjected to vacuumdistillation. The residual substantially colorless oil so obtained isidentified as l-anti-trans-l,8adimethyl-A -decahydrophenanthren- 2-one,the yield being substantially The first step of the method of thisinvention is the formylation of the dihydro tricyclic ketone (CompoundII) to give a hydroxy methylene compound of the structural formula HOHThe hydroxy methylene compound (Compound III) is readily prepared byreacting ethyl fonnate with the corresponding dihydro tricyclic ketone(Compound II) in the presence of sodium methylate. As illustrative ofthis step is the following:

Example III Weight of water and 45 parts by weight of acetic acid in 190parts by weight of water while maintaining the temperature below 30 C.The mix is agitated for about 30 minutes and the aqueous layerseparated. The aqueous layer is extracted with several small portions ofbenzene. The benzene extracts are then combined with the originalorganic layer and the combined mix subjected to vacuum distillation. Thebrown oily residue is taken up with 70 parts by weight of heptane. Uponcooling to about C. yellow crystalline l-anti-trans-1,8a-dimethyl,3-(hydroxy)- methylene, A -decahydrophenanthren 2 one separates. Thecrystalline material is recovered and dried and its melting point foundto be 99.5100.5 C. The yield is 86% by weight.

Simlarly d-anti-trans-1,8a-dimethyl, 3-(hydroxy)methylene, A-decahydrophenanthren-Z-one (M. P. 99.5- 100.5 C.) is prepared fromd-anti-trans-l,Sa-dimethyl, A -decahydrophenanthren-Z-one.

Employing the same procedure as in Example III above but replacingl-anti-trans-1,8a-dimethyl, A -decahydrophenanthren-Z-one with anequimolecular amount of dl-anti-trans 1,8a- -dimethyl, A-decahydrophenanthren-Z-one an excellent yield of yellow crystallinedlanti-trans-l,8a-dimethyl, 3-(hydroxy)n1ethylene, Adecahydrophenanthren-2-one (M. P. 83-845 C.) is obtained.

The second step of the method of this invention is the conversion of thehydroxy methylene compound (Compound III) to the methylanilino compound(Compound IV). The methylanilino compound (Compound IV) is readilyprepared by condensing the corresponding hydroxy methylene compound(Compound III) with N- methylaniline. As illustrative of this step isthe following:

Example IV collected yellow crystalline product washed with methanol.The product is dried and identified as dl-anti-trans- 1,8a-dimethyl,3-(N-methylanilino) methylene, A decahydrophenanthren-Z-one (M. P.124.4125.9 C.). The yield is 90% of theory.

Example V To a suitable reaction vessel containing 38.9 parts by weightof l-anti-trans-1,8a-dimethyl, 3-(hydroxy)methylene, A-decahydrophenanthren-2-one dissolved in 177.6 parts by weight ofmethanol is slowly added and intimately mixed 40.4 parts by weight ofN-rnethylaniline while maintaining the temperature during the additionat about C. The mix is agitated for about 16 hours while permitting thetemperature to drop to room temperature. The methanol solvent andunreacted N-methylaniline is then distilled ofl under reduced pressure.The yellow oily product so obtained is identified asl-anti-transl,8a-dimethyl, B-(N-methylanilino) methylene, Adecahydrophenanthren-Z-one. The yield is 85% of theory.

Employing the same procedure as in Example V but replacingl-anti-trans-l,8a-dimethyl, 3-(hydroxy) methylene, A-decahydrophenanthren-Z-one with an equimolecular amount ofd-anti-trans-l,8a-dimethyl,- 3- (hydroxy) methylene, A-decahydrophenanthren-2- one an excellent yield ofd-anti-trans-1,8a-dimethyl, 3-(N- methylanilino) methylene, A-decahydrophenanthren-Z-one is obtained.

The next step in the method of this invention is the formation of thel-(fl-cyanoethyl) .substituted methyla'nilino derivative of thehydroxy-methylene dihydro tricyclic ketone (Compound V). In itspreparation a new asymmetric center is introduced and thus a mixture ofstereoisomers results. This mixture is preferably not isolated andseparated into its isomeric parts, but converted directly by vigorousbase hydrolysis to the corresponding carboxy ethyl derivative (CompoundVI). The carboxy ethyl derivative so obtained is a mixture of isomericketo acids, which isomers for purposes of this invention may berepresented structurally and identitled as follows:

CHa T113 l T l 0 Hooo d a keto acid )3 keto acid While both of theisomeric a and [3 keto acids may be converted to a tetracyclic ketone ofthe general structure of Compound VIII, only the fl-keto acid asidentified herein produces a tetracyclic ketone corresponding inconfiguration to that of the l7-aldehyde steroid.

As illustrative of the preparation of the keto acid (Compound V1) is thefollowing:

Example VI To a suitable reaction vessel containing parts by weight ofdl-anti-trans-1,8a-dimethyl, 3(N-methylanilino) methylene, A,-decahydrophenanthren-2-one dissolved in 1360 parts by weight of tert.butyl alcohol is added and intimately mixed 60 parts by weight ofacrylonitrile and 18 parts by weight of 40% aqueous benzyl trimethylammonium hydroxide in 39 parts by weight tert. butanol and 5 parts byweight water. The air of the system is replaced by nitrogen and thereaction mix is heated at 5055 C. for about 44 hours. The system is thencooled and the catalyst neutralized with 2.5 parts by Weight of aceticacid. The tert. butyl alcohol is then removed under vacuum at a maximumtempera ture of 50 C. and a final pressure of 2 mm. To the oily residueso obtained is added 325 parts by weight of water and 450 parts byweight diethyl ether. The mixture is stirred for one-half hour' and thenthe ether layer separated. The aqueous layer is extracted with 225 partsby weight of ether and the ether extract combined with the originalether layer. The solution is then extracted twice with 500 parts byweight of 10% hydrochloric acid and twice with 100 parts by weight ofWater. The ether is evaporated and the residue dissolved in a solutionof parts by weight potassium hydroxide in 1000 parts by weight water.The resultant solution is extracted with 80 parts by weight of ether toremove alkali insolubles and then refluxed at 100-102 C. for ten hoursunder an atmosphere of nitrogen. The alkali solution of dl-keto acids isthen cooled and extracted with 160 parts by weight of ether. The aqueousphase is then acidified with parts by weight of 35% hydrochloric acid.The precipitated keto acids are filtered off and extracted With three240 parts by weight portions of ether. The extracts are combined andwashed with two 250 parts by weight portions of water. Upon evaporatingthe ether solvent there is obtained 74.3 parts by weight of crudedl-keto acids. This crude which contains a weight ratio of a-isomer tofl-isomer of approximately 3 :1 is then taken up with warm ether andallowed to stand for about 20 hours. The white crystalline B-isomer ofthe dl-keto acid separates leaving the u-isomer in solution. The whitesolid pisomer is filtered oif and is found to have a melting point inthe range of 170-172 C. The yield of the fi-isomer of the dl-keto acidis 22.2%.

Employing the same procedure as in Example VI but replacingdl-anti-trans-1,8a-dimethyl, 3 (N methylanilino) methylene, Adecahydrophenanthren-2- one with an equimolar amount ofl-anti-trans-1,Sa-dirnethyl, S-(N-methylanilino) methylene, M'-decahydrophenanthren-Z-one there is obtained an oil containing thea-isomer and B-isomer of the l-keto acid in a yield of about 90% oftheory. The weight ratio in the resultant product of a-isomer tofi-isomer is about 3:1.

The next step in the method of this invention is the conversion of theketo acid (Compound VI) to the enol lactone (Compound VII) by boilingthe former with acetic anhydride in the presence of a small amount ofsodium acetate. As illustrative of this step is the following:

Example VII 30.76 parts by weight of the 5 form of dl-anti-trans-1,8a-dimethyl, l-(fi-carboxy ethyl), A -decahydrophenanthren-Z-one isadmixed with 0.15 parts by weight of anhydrous sodium acetate and 248.4parts by weight of acetic anhydride and the mixture refluxed for about 4hours in an atmosphere in nitrogen. The acetic anhydride is removedunder reduced pressure. Thereafter the residue is taken up with diethylether. The ether solution is washed with aqueous sodium bicarbonatesolution and then with Water. The ether solution is then cooled to C.whereupon white crystalline dl-3-l eto-A 4-oxa-Dhomoandrostatrienehaving a melting point of about 99.8101.2 C.

CH3 CH;

Example VIII 17.9 parts by weight of a crude oil mixture of the or and Bisomers of l-anti-trans-l,8a-dimethyl, l-(fl-carboxyethyl), A-decahydrophenanthren-Z-one (weight ratio of OC-iSOmel' to tr-isomerbeing about 3:1) is dissolved in 208 parts by weight of acetic anhydridecontaining 0.1 part by Weight of anhydrous sodium acetate and themixture refluxed for 4 hours in an atmosphere of nitrogen. Uponstripping oil the acetic anhydride a light brown oily residue isobtained. The residue is taken up with ether and filtered. The filtrateis subject to reduced pressure whereupon the ether distills ofi leaving13 parts by weight of an oil containing approximately 3.3 parts byweight of l-3-keto-A -4-oxa-Dhomoandrostratriene (B-l-enol lactone).

The next step in the method of this invention is the preparation of thetetracyclic ketone (Compound VIII) from the enol lactone (Compound VII)by reacting the latter With a methyl magnesium halide in diethyl ether,decomposing the addition product with dilute mineral acid, and thentreating the ether solubles with an alcohol solution of an alkali metalhydroxide. As illustrative of this step is the following:

Example [X To a solution of 21.5 parts by weight of cll-3-keto- A-4-oxa-D-homoandrostatriene (B-dl-enol lactone) in 160 parts by weightof benzene and 800 parts by weight of ether is added over a period ofabout ten minutes a solution of 18.1 par-ts by weight of methylmagnesium bromide in 280 parts by weight of ether While maintaining thetemperature of the system at about 55 C. and under an atmosphere ofnitrogen. Upon completion of the methyl magnesium bromide addition themix is agirated at -55 C. for about one hour. To the cold mix soobtained is added 300 parts by Weight of an ice cold 6.5% hydrochloricacid and the mix agitated at 0 C. for about 15 minutes. The aqueouslayer is separated and washed with several small portions of diethylether. The ether extracts and the original organic layer are combinedand the ether evaporated. The residue is then taken up wit-h 1200 partsby weight of methanol and thereto is added 18 parts by weight of sodiumhydroxide dissolved in 180 parts by weight of water. The mix so obtainedis refluxed for about 2 hours in an atmosphere of nitrogen. The mix isthen cooled and most of the methanol evaporated under vacuum. Then 40parts by weight of water is added and the aqueous layer extracted withseveral portions of ether. The ether extracts are combined and washedtwice with water. The ether layer is then subjected to distillation andthe solid residue (19.3 parts by weight) after recrystallization frommethanol yields white crystalline .dl-3keto-A -D horrroandrostatrienehaving a melting point of about 144-146" C. The yield of fl-dltetracyc'lic ketone is of theory.

Employing the same procedure as in Example IX but replacing dl-3-keto-A4oxa-Dhornoandrostatriene With an cquimolecular amount of the B-isomerof the l-enol lactone, namely, [-3- xetc-A -4-oxa-D-homoandrostatriene,there is obtained an 85% yield of white crystalline l-3keto-A-D-homoandrostatriene having a melting point of about 174175 C.

The fi-isomer of d-tetracyclic ketone, namely d-3-keto- A-D-homoandrostatriene (melting point of about 174-175 C.) is similarlyproduced beginning with the fl-isomer of the d-enol lactone, namely,d-3-keto- A -4-oxa-D-homoandrostatriene.

Another means of preparing the fi-isomer of the l-tetracyclic ketone isas follows:

Example X 49.7 grams of the crude oil of Example VIII which containedapproximately 25% by weight of the /3-isomer of l-enol lactone isdissolved in 2500 cc. of diethyl ether and cooled to 55 C. Approximately250 cc. (about 5.7 molar equivalents) of methyl magnesium bromide isadded over about 15 minutes while keeping the temperature below 50 C.The reaction system is maintained at 50 C. for about 1 hour and 15minutes after the addition of the Grignard reagent. Thereupon cc. ofacetone is added to use up the excess Grignard reagent. The solution isthen acidified with 250 cc. of concentrated hydrochloric acid dilutedwith about 800 cc. of water. The organic layer is separated andconcentrated by evaporation. The heavy dark oily colored residue is thendissolved in 1600 cc. of methyl alcohol and admixed with 2.5 parts byweight of sodium hydroxide dissolved in 100 cc. of Water. The solutionso obtained is refluxed under an atmosphere of nitrogen for 2 hours andthen the solvent partially removed under reduced pressure. Theconcentrated liquor is reduced to a volume of about 200 cc. Thereupon800 cc. of water and 800 cc. of diethyl ether is added and the mixtureagitated vigorously and then allowed to stand over night. The layers areseparated. The aqueous layer is filtered to remove the granular solid.This material upon recrystallization is a white needle-like crystallinematerial identified as the B-isorner of l-tetracyclic ketone having amelting point of about 174-175 C. The aqueous filtrate is extracted withseveral small portions of ether and the extracts combined with theoriginal ether layer and allowed to stand in the cold. The crystallinesubstance separating therefrom is isolated and dissolved in methanol. Tothe methanol solution is added a solution containing 5 parts by weightof semi-carbazidehydrochloride and 5 partsbyweight-of sodium acetate inneutralized to a pH of with potassium hydroxide.

40 cc. of methyl alcohol. The mixture is agitated and filtered. Thefiltrate is heated on -a steam bath for 45 minutes during which time thesemi-carbazone of the fi-isomer of l-tetracyclic ketone separates. Thesolution is cooled and filtered yielding 5.6 parts by weight of a lightyellow crystalline solid having a melting point of 245-248 C. The solidmaterial so obtained is admixed with 750 cc. of heptane and 750 cc. of2-N hydrochloric acid and refluxed for about 3 hours. The organic layeris separated and the solvent is dis-tilled off under reduced pressure.The crystalline residue so obtained is washed with methyl alcoholleaving 3.34 grams of white crystals of the fl-isomer of l-tetracyclicketone (melting point of about 174-175" C.).

In the next step of the method of this invention the tetracyclic ketone(Compound VIII) is converted to the 16,17-glycol (Compound IX) bytreatment of the former with silver acetate and iodine. The 16,17-glycol(Compound IX) so obtained is to be distinguished from the 3 keto 16,17dihydroxy A D homoandro stadiene described by R. B. Woodward, I. A. C.8., vol. 74, p. 4223if. Both the 16,17-glycol (Compound IX) of thisinvention and Woodwards 3-keto-16,17-dihydroxy- A- -D-homoandrostadieneare cis-glycols, however, with respect to the plane of the nuclearcarbon atoms of the cyclonexyl ring the hydroxy substituents ofWoodwards compound are below the plane whereas in the 16,17-glycol ofthe present invention the hydroxy substituents are above the plane ofthe nuclear carbon atoms. As illustrative of this step is the following:

Example XI 28 parts by weight of dl-3-keto-A -D-homoandrostatriene(ti-form of dl-tetracyclic ketone) is dissolved in 800 parts by weightof glacial acetic acid and thereto is added and intimately mixed 38.2parts by weight of silver acetate and 25.3 parts by weight of iodine.Upon agitating the mix so obtained for one hour at 20-25 C. 1.8 parts byweight or" water is added and the mix heated to 90-95 C. and maintainedat that temperature for three hours. The reaction mix is cooled andfiltered and the filtrate subjected to vacuum distillation to remove thebulk of the acetic acid solvent. The residue is then taken up with 500parts by weight of methyl alcohol and To the solution so neutralized isadded 90 parts by weight. of an 11% by weight methyl alcohol solution ofpotassium hydroxide and the mixture allowed to stand for about 16 hoursat 20-25 C. under an atmosphere of nitrogen. The solution is thenneutralized with 35% hydrochloric acid. The neutralized solution is thensubjected to vacuum distillation. The residue is then dissolved in 1000parts by weight of chloroform and the solution washed with several smallportions of water. The chloroform solution is then dried over magnesiumsulfate and filtered. The filtrate is then subjected to vacuumdistillation to remove the solvent. Upon recrystallization of theresidue from methyl alcohol there is obtained 21.3 parts by weight ofthe white crystalline dl-3-keto-16,17-dihydroxy- A -D-homoandrostadiene(M. P. 215-218 C.).

Employing the same procedure as above but replacing the dl-3-keto-A-D-homoandrostatriene with an equimolar amount of the l-3-keto-A-D-homoandrostatriene (IQ-isomer of Z-tetracyclic ketone) there is obtained an excellent yield of l-3-keto-16,17-dihydroxy- A-Dhomoandrostadiene (M. P. 185-187 C.).

Similarly d-3-keto-16,17-dihydroxy-A -D-homoandrostadiene (M. P. 185-187C.) is obtained from the fi-isomer of d-tetracyclic ketone.

The next step of this invention is the preparation of the dialdehyde(Compound X) via the oxidation of the glycol (Compound IX) with periodicacid, which compound is preferably not isolated but heated in solution.in the presence of piperidine acetate to reclose ring D to 10 give the17 aldehyde steroid (Compound XI). As illusnative of this step is thefollowing Example XII 45 parts by weight of dl-3-keto-16,17-dihydroxy, A-D-homoandrostadiene is dissolved in 2000 parts by weight of dioxane.Thereto is added a solution of 45 parts by weight of periodic aciddihydrate in 800 parts by weight of water. The so obtained is agitatedat 0 C. under an atmosphere of nitrogen for 14 hours. T hereupon thedioxane is distilled off under reduced pressure and the residue taken upwith water. The aqueous phase is then extracted with several parts byweight portions of ether. The ether extracts are combined and washedwith a 5% aqueous sodium carbonate solution. The organic layer is thendried over magnesium sulfate and filtered. Upon removing the ether fromthe filtrate so obtained the residue is dissolved in 2500 parts byweight of benzene. To the solution so obtained is added 20 parts byweight of acetic acid and 10 parts by weight of piperidine and the mixso obtained heated at 60 C. for one hour in an atmosphere of nitrogen.The resultant mix is cooled and washed successively with 5% hydrochloricacid, 5% aqueous sodium carbonate, and finally with water. The benzenelayer is then dried over magnesium sulfate and filtered. The solution isevaporated to dryness and upon recrystallizing the residue from benzenethere is obtained 28 parts by weight of white crystalline dl Agulhlfibisdehydro norprogesterone (M. P. 178- 17 85 C.).

Employing the same procedure as above but replacing thedl-3-keto-16,17-dihydroxy, N D -homoandrostadiene with an equimolaramount of l-3-keto-16,17-dihydroxy, A -D-homoandrostadiene an excellentyield of white crystalline l-A -bisdehydro-norprogesterone (M. P. -158"C.) is obtained.

It is to be understood that the invention is not limited to the exactdetails of operation of the compounds shown and described, since obviousmodifications and equivalents.

will be apparent to those skilled in the art and are to be construed tobe within the spirit and scope of this invention.

What is claimed is:

1. The process which comprises (a) reacting 1,8a-dimethyl-M-decahydrophenanthren-Z-one with ethyl formate in the presence of sodiummethylate, (b) reacting the 1,8a-dimethyl-3-(hydroxy) methylene-A-decahydrophenanthrene-2-one so obtained with N-methylaniline, (c)reacting the 1,8a-dimethyl-3-(N-methylanilino methylene-13decahydrophenanthren-2-oneso obtained with acrylonitrile under alkalineconditions and (d) converting the adduct so obtained by vigorousalkaline hydrolysis to 1,Sa-dimethyl-l-(fi-carboxyethyl)- A-decahydrophenanthren-2-one.

2. 1,8a-dimethyl, 3-(hydroxy) methylene, A decahydrophenanthren-Z-one.

3. 1,821 dimethyl, 3 (N methylanilino) methylene, A-decahydrophenanthren-Z-one.

4. l-(B-carboxyethyl)-1,8a-dimethyl, phenanthren-Z-one.

5. The anti-trans isomers of the compound of claim 2.

A -decahydro- 6. dl-Anti-trans- 1 8a-dimethyl,3 -hydroxy) methylene, A-decahydrophenanthren2-one.

7. l-Anti-trans-1,8a-dimethyl,3-(hydroxy) methylene, A-decahydrophenanthren-2-one.

8. d-Anti-trans-l,8a-dimethyl,3-(hydroxy) methylene,

A -decahydrophenanthren-Z-one.

9. In the method of making the compound of claim 2 the step whichcomprises reacting 1,8a-dimethyl, M decahydrophenanthren-Z-one withethyl formate in the presence of sodium methylate.

10. In the method of making the compound of claim 6 the step whichcomprises reacting dl-anti-trans-1,8adimethyl, A -decahydrophenanthren 2one with ethyl formate in the presence of sodium methylate.

11. In the method of making the compound of claim 7 the step whichcomprises reacting lrantirtrans-lfla-dimethyl, A-decahydrophenanthren-Z-one with ethyl formate in the presence of sodiummethyiate.

12. In the method of making the compound of claim 8 the step whichcomprises reacting d-anti-trans-1,8a-dimethyl, A-decahydrophenanthren-2-one with ethyl formate in the presence of sodiummethylate.

References Cited in the file of this patent

1. THE PROCESS WHICH COMPRISES (A) REACTING1,8A-DIMETHYL-$6,10A(1)-DECAHYDROHENANTHREN-2-ONE WITH ETHYL FORMATE INTHE PRESENCE OF SODIUM METHYLATE, (B) REACTING THE1,8A-DIMETHYL-3-(HYDROXY)METHYLENE-$6,10A(1)-DECAHYDROPHENANTHRENE-2-ONE SO OBTAINED WITHN-METHYLANILINE, (C) REACTING THE 1,8A-DIMETHYL-3-(N-METHYLANILINOMETHYLENE-$6,10A(1) - DECAHYDROPHENANTHREN-2-ONE SO OBTAINED WITHACRYLONITRILE UNDER ALKALINE CONDITIONS AND (D) CONVERTING THE ADDUCT SOOBTAINED BY VIGOROUS ALKALINE HYDROLYSIS TO1,8A-DIMETHYL-1-(B-CARBOXYETHYL)$6,10-DECAHYDROPHENANTHREN-2-ONE.